Mercurated alkyl amides of dibasic phenylene acids and homologues thereof



Patented Feb. 16, 1943 UNITED STATES PATENT OFFICE MERCURATED'ALKYL AMIDES OF DIBASIC PHENYLENE: ACIDS AND HOMOLOGUES THEREOF Donalee: L, Tabern, Lake Blufi, 111., assignor to Abbott Laboratories, North Chicago, 111., a cor poration of Illinois No Drawing. Original- Serial .No- 273,725.

application May 15,.- 19-39,

Divided and this application June 1, 1942, Serial No. 445,318

cal compositions and has for itsprincipalobject the preparation of novel compounds possessingl properties making them adaptable for use in the diuretic field. A more specific object ofthe present invention is to provide mercurated. alkyl amides of dibasic phenylene acids possessing diuretic activity of the type desired;

Certain types of mercury compoundsin which. the mercury group is attached to either. anim. organic or organic radical, have the property of, producing diuresis. Inorganiccompounds of. mercury, however, are highly toxic and;the.ratio.be* tween the effective dose and the toxicdoseis such. as to preclude their effective use-intherdiuretic field. The same difiiculty exists in thez case ofmost organic compounds of mercury, which are either too high in toxicity or too low in the desired therapeutic efiectivenessforuse in the-medical art.

I have discovered thatmercury derivativesof alkylamides of dibasic aromatic: acids, esp'ecial1y mercurated propyl amides of phthalic acid, are particularly efiective diuretics, because of their high. efiiciency and relatively low toxicity. In other Words, the compounds of the present invention possess a low diuretic dose and the ratio of the eifective therapeutic dose to they toxic dose unusually high. Of great importance, thenew compounds are well tolerated during repeated.injections. In addition, the compounds included in. the present invention are soluble (or capable of being solubilized) and form stable solutions particularly adaptable for hypodermical administration.

The dibasic aromatic acids suitable for use: the present invention may be illustrated by the following general formula:

C-Ra

in which R1 represents an aromatic ring such as the phenyl group;

in which R2 represents (a) Hydroxyl (OH) group.

(b) Salt O-metal group such as --ONa and in which R3 represents an active alkylene amide group such as ally] group in which Z represents ahydrogen atom, saturated and unsaturated alkyl groups.

allyl group, where W represents-a whole number.

The followingspecific examples of reactive alkylene amides ofiprithalicacid derivatives coming within the scope of :the present invention will serve for. illustrative purposes: Y i

1. Mbnoallylnmidewofi phthalic acithv 0 allyl- 2. Monoallyl amideof: sodium phtha-late:

13:. b- T c") 511y1 3. Di-allyl amide of sodium phthalate.

4. Monoallyl ureide of sodium phthalate.

H erotonyl with saturated and unsaturated alkyl groups and hydroxy alkyl groups. Examples of such reactive alkylene amides are;

6. Bis-monoallylamide of terephthalic acid.

H C-lh-allyl C-N t \m 7. Monobutenyl amide; methyl, amyl amide of phthalic acid.

0 CH3 J-N-CsHu 5 O 1 butenyl An 'de derivatives of this type form the subject matter of my co-pending application Serial No.

273,725. The present application directed to the acid and salt derivatives is a divisional application of Serial No. 273,725,,Patent No. 2,300,992.

In the above formulas each compound has at least one unsaturated or alkylene amide group (N alkylene group, e. g. allyl) which is capable of reacting with a mercury salt such as mercuric acetate, mercuric sulfate, etc. to yield mercuration products. When the parent compound has one alkylene or reactive group it is reacted with one mol. of mercury salt to form a mono-mercurated product, and when the parent compound has two or more such groups it is reacted with one, two or the corresponding mols of mercury salt to form monoor di-mercurated products.

The mercuration carried out 11113. suitable aqueous solvent with mercuric acetate results in the formation of mercurated alkyl groups of which the following formulas are illustrative:

H .H v A r-emotion: flI-OihCHcH;

00011; or 012,005 i i ooccni cmcoo g By natural hydrolysis, by neutralization with alkali, or by evaporation in vacuo the acetoxy groups are gradually eliminated being replaced by hydroxy groups resulting the formation of mercurated alkyl groups of which the following formulas are illustrative:

- sponding acid radical or OCO alkyl group) may resented by the above formula.

bond saturated by -HgOH and OH groups.

If, as it is frequently desirable to carry out mercuration in an organic solvent such as methyl alcohol, the final product may have a OCI-Iz s r group (depending on the alcohol used) in place of In the general formula above R2 may also be an amide group including amide roups substituted the -OH group attached to the alkyl. group rep- Other liquids, such as ether, etc., may likewise be employed for the mercuration reaction.

If desired, the mercuration products may be isolated as more or less crystalline solids by concentration in vacuo, and purified by washing with ether or in the'case of those insoluble in dilute acids, by suitable acidification. The soluble products obtained in an aqueous reaction medium may be diluted to the proper concentration and used without isolation. The products containing a free carboxy group (i. e. those containing'no solubilizing group such as ONa, NHz) are usually sparingly soluble and are dissolved by the addition of the requisite quantity of alkali.

The following examplesdescribing the preparation'of the alkylene amide intermediates and the preparation of the mercuration products therefrom will. serve for illustrative purposes:

' EXAMPLE I Mono-mercuratecZ-propylamide, allylamide of phthalic acid washed with dilute alkali and recrystallized from alcohol. This product, bis-monoallylamide of phthalic acid, melting sharply at 133-135 C.,'

may also be prepared by reacting ethyl phthalate (preferably with gentle heating) with an excess of allylamine.

If desired, the original preparation with the acid chloride may be carried out in an aqueous medium by replacing two of the mols of allyl-amine with an equivalent of sodium hydroxide.

The mercuration reaction may be advantageously carried out in water solution as follows: About 25 grams of bis-monoallylamide of phthalic acid prepared, for example, by one of the methods described above, are suspended in about a liter of water and treated slowly, with good stirring, with about 31.5 grams-of mercuric acetate. The completion of the reaction may be determined by the absence of the customary tests for the pres- ,ence of ionic mercury (e. g. no precipitate with may be separated from the reaction mixture by filtration. If desired, a mixture of equimolecular amounts of freshly precipitated mercuric oxide and mercuric acetate may be employed for mer: curation. The temperature during the reaction may vary from -95 C. without appreciably changing the course of the reaction or the mercuration product produced.

The aqueous solution prepared as above may be used directly after proper dilution for the production of diuresis. In practice it has been found advantageous to partially or completely neutralize the solutions with a base such as sodium hydroxide or ammonium hydroxide. Solutions having pH values of about 6-8 are of increased stability and assist in preventing irritation at the site of injection.

The mercuration reaction may alsobe carried out in a suitable organic solvent such as methyl alcohol. In this case after the complete removal of the solvent, the solid remaining should be washed with ether. This product dissolved in water gives a solution having the same physiological properties as the mono-mercurated reaction product obtained in the aqueous medium described above.

EXAMPLE II Mono-mercurated mono-propylamz'de of phthalic acid The intermediate product may be prepared by adding about 1 mol. of allylamine to about 1 mol.-

of finely powdered phthalic anhydride suspended in benzene. The reaction is instantaneous and monoallylamide of phthalic acid separates in excellent yield. This product may be purified by extraction with considerable volume of dry ether or dissolved in sodium hydroxide solution and precipitated by addition of acid. The purified product melts at 110-112 C.

The mercuration reaction, as indicated in Example I, may be carried out in a number of ways. The following (one of the preferred methods) will serve for illustrative purposes:

To about 20.5 grams of monoallylamide of phthalic acid dissolved in methyl alcohol is added a methyl alcohol solution containing about 31.6 grams of mercuric acetate. After the reaction is complete, the solvent is largely evaporated and the residue then poured into a substantial volume of ethe Analysis of the granular mass which settles out indicates the product to have the following formula:

(fi-N-CHr-OH-CH. o Hg H E This product may be solubilized by treatment with one equivalent of alkali hydroxide, e. g, sodium or potassium hydroxide. The alkali salt dissolves readily in water to form stable solutions adaptable for hypodermical administration.

EXAMPLE III Mono-mercurated monopropyl ureide of phthalic acid Monoallyl urea and phthalic anhydride in molecular quantities are fused at about 120 C. to form the corresponding allyl ureide melting at 168-1'l0 C. This product is then mercurated in an aqueous solution with mercuric acetate, sufiicient alkali being added from time to time to maintain a clear solution. At the end of several days standing a small precipitate forms which may be separated by filtration. The reaction is complete when the clear solution fails to give an immediate dark precipitate with hydrogen sulfide.

In this example the i N-alkylene group is part of a complex substituent. compounds represented by the formula I T-(CH2)wC l q-alkylene where w equals 0 or 1, 2, 3, etc. are also included within the scope of the present invention. Where w is zero (0) the compound is a ureide prepared from urea as described above. In the following group to equals 2, --NHCI-IzCH2COI-IN allyl.

It will be obvious to those skilled in the art that the present invention is not limited to the above illustrative examples. The scope of the present invention is accordingly to be determined by the claims annexed hereto.

In the specification and claims it will be obvious that the acy1 group of a dibasic acid may be represented by'the following formula COOH l where'Rn represents the phenylene radical. It will also be obvious that the alkylene group of the amide is saturated and forms a mercurated alkyl group after mercuration. I claim: 1. A compound selected from the group consisting of mercurated alkyl amides of dibasic aromatic acids and salts thereof in which the acids are represented by the following formula Other in which R1 is selected from the group consisting of phenylene and homologues thereof, and R3 represents the mercurated alkyl amide group.

2. A mercurated alkylene amide of an aromatic dibasic acid, the mercury group being attached to the alkylene group of said amide so as to sa urate the alkylene group, and the aromatic group of the dibasic acid being selected from the group consisting of phenylene and homologues thereof.

3. A compound having the following formula:

R-NHOHzCH OH:

in which R represents an-acyl group of a phenylene dibasic acid and in which one of the R's is selected from the group consisting of HgOH and HgOCOA and the other H is selected from the group consisting of OH and OCOA, in which the A's represent alkyl groups.

4. A compound having the following formula:

RNHCH2CH CH2 RI I in which R represents an acyl group of phthalic acid and in which one of the R's is selected from the group consisting of HgOH and I-IgOCOCH:

and the other R is selected from the group consisting of OH and OCOCH3. .i

5. A compound having the following ormula:

. fi I t I C-0alka1ir uetai i |T|JNHCH2CH CH: 0 R R in which one of the R's is selected from the group consisting of HgOI-I and; HgOCOCI-Ia and the other R is selected from the group consisting of OH and OCOCH3.

6. A stable diuretic composition comprising an aqueous solution containing a compound having the following formula: l

CONHCHnCH 0H1 v HgOH said. solution having a pH value of 6-8.

DONALEE L. TABERN. 

